The KU Center for Excellence in Chemical Methodologies and Library Development (KU CMLD), now in its fifth year of operation, has firmly established itself as a resource for parallel synthesis of chemical libraries in the US Midwest. In the previous funding period, vital cores for library synthesis as well as library design, analysis, and purification (LDAP) were established. The synthesis core has facilitated library synthesis by providing technology and library expertise to the group of CMLD researchers, while the LDAP core established protocols for in silico evaluation/database maintenance and the mass-directed purification of compounds. The infrastructure made possible through the CMLD program has also benefited the larger scientific community by providing these critical services to researchers outside the CMLD grant per se (e.g., to several groups maintaining separate Pilot Scale Library programs). Following a period of growth, the impact of the KU CMLD center has been established through ca. 60 scientific publications, steadily increasing submission of high-quality compounds to the Molecular Libraries Small Molecule Repository (MLSMR), and biological validation through collaborations with the MLSCN and eight additional biological evaluators that have yielded novel hits from various CMLD research programs. The present application for renewal of the KU CMLD presents programs that will build on its existing strengths and bring the program into new directions. Consistent with its adopted mission of enabling library synthesis as broadly as possible, a series of projects involving seven investigators at four academic institutions is described. Three of the four projects address the synthetic challenges inherent in library construction. These range from C-H functionalization reactions of phenols to Pd-promoted multicomponent reactions to the strategic deployment of a sulfonamide-forming click reaction. The fourth project concerns the development of protocols and technology for carrying out microwave-assisted flow synthesis. Finally, we stand firm in our commitment to provide novel compounds to the MLSMR at the estimated rate of 1800 compounds/year and to follow up on our chemical methodology work by doing all that we can to ensure our compounds will have a positive impact on biomedical science.